Young Hwa Chung

Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion

Background and Aim:  This study aimed to evaluate the therapeutic efficacy and safety of repeated transarterial chemoembolization (TACE) with additional radiation therapy (RT) in hepatocellular carcinoma (HCC) with portal vein (PV) invasion.

Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.

Primary liver cancer is the third most common cause of cancer‐related death worldwide, with a rising incidence in Western countries. Little is known about the genetic etiology of this disease. To identify genetic factors associated with hepatocellular carcinoma (HCC) and liver cirrhosis (LC), we conducted a comprehensive, genome‐wide variation analysis in a population of unrelated Asian individuals. Copy number variation (CNV) and single nucleotide polymorphisms (SNPs) were assayed in peripheral blood with the high‐density Affymetrix SNP6.0 microarray platform. We used a two‐stage discovery and replication design to control for overfitting and to validate observed results. We identified a strong association with CNV at the T‐cell receptor gamma and alpha loci (P < 1 × 10−15) in HCC cases when contrasted with controls. This variation appears to be somatic in origin, reflecting differences between T‐cell receptor processing in lymphocytes from individuals with liver disease and healthy individuals that is not attributable to chronic hepatitis virus infection. Analysis of constitutional variation identified three susceptibility loci including the class II MHC complex, whose protein products present antigen to T‐cell receptors and mediate immune surveillance. Statistical analysis of biologic networks identified variation in the “antigen presentation and processing” pathway as being highly significantly associated with HCC (P = 1 × 10−11). SNP analysis identified two variants whose allele frequencies differ significantly between HCC and LC. One of these (P = 1.74 × 10−12) lies in the PTEN homolog TPTE2. Conclusion: Combined analysis of CNV, individual SNPs, and pathways suggest that HCC susceptibility is mediated by germline factors affecting the immune response and differences in T‐cell receptor processing. (HEPATOLOGY 2010)

p16 Hypermethylation in the early stage of hepatitis B virus- associated hepatocarcinogenesis

Abnormality of the p16 expression is involved in the pathogenesis of hepatocellular carcinoma (HCC), and hypermethylation of p16 gene is known as a major p16 inactivation mechanism. Cirrhotic nodule (CN) is now regarded as a preneoplastic lesion that is frequently associated with microscopic foci of HCC through dysplastic nodules (DNs). This observation clearly supports a multistep hepatocarcinogenesis from CNs through DNs. We thus examined the methylation status of p16 gene in HCCs surrounded by DNs and CNs to define the significance of p16 hypermethylation in the early stage of hepatocarcinogenesis. We tested 24 hepatitis B virus (HBV)-associated CNs, 37 DNs, and 18 HCCs within DNs that were microdissected from paraffin-embedded tissue sections. Frequency of p16 hypermethylation was significantly high in HCCs within DNs (15/18. 83.3%) and it increased from CNs (15/24. 62.5%) through DNs (26/37, 70.3%). Interestingly, 11 out of 12 (91.7%) HCC associated with methylation-positive DNs revealed hypermethylation of p16, and 18 out of 23 (78.2%) DNs associated with methylation-positive CNs showed p16 hypermethylation. These data suggest that p16 hypermethylation in the early stages, CNs and DNs may predispose to HCC. In addition, p16 methylation status of five cell lines with or without HBV infection was examined to test whether the high frequency of hypermethylation is related to HBV infection. HBV-infected cell lines were exclusively methylation-positive. These data suggest that high frequency of hypermethylation may be associated with hepatitis B virus infection.

HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C VIRUS INFECTIONS IN KOREAN PATIENTS WITH HEMATOPOIETIC MALIGNANCIES

We performed a large case–control study (3,932 cases, 15,562 controls) to investigate the association of hepatitis B virus (HBV) and hepatitis C virus (HCV) with hematopoietic malignancies in Korea, where HBV is endemic. HBV was present in 636 control patients (4.1%), 333 lymphoma patients (12.4%), and 75 leukemia patients (6.0%). HCV infection was present in 173 control patients (1.1%), 76 lymphoma patients (2.8%), and 18 leukemia patients (1.4%). Co-infection of HBV and HCV was present in one (0.007%) control patient, seven lymphoma patients (0.3%), and one leukemia patient (0.08%). HBV infection was associated with increased risks for most subtypes of B and T/NK-cell lymphomas, Hodgkin’s lymphoma, and acute myeloid leukemia. HCV infection was associated with increased risks for diffuse large B cell lymphoma, extranodal marginal zone B cell lymphoma, peripheral T cell lymphoma, and acute lymphoid leukemia B cell early pre-B type. HBV seems to have a more important role than HCV in the pathogenesis of specific hematologic malignancies in Korea.

Epidemiology of hepatocellular carcinoma in Japan and Korea

The worldwide burden of liver cancer has been estimated at 671,000 new cases for the year 2005. Hepatocellular carcinoma (HCC) accounts for between 85 and 90% of primary liver cancer and is one of the most frequent malignancies in Asia. In both Japan and Korea, the incidence exceeds 25 cases/100,000/year and ranks third in cancer deaths after stomach and lung cancer. In Korea the number of deaths from liver cancer increased from approximately 5,789 in 1983 to 9,966 in 1994, and then remained steady at 9,500/100,000 in 2003. In Japan the number of deaths from HCC increased until 2002, and then decreased to 34,089 in 2003, up to 15% of HCC cases are caused by hepatitis B virus (HBV) and ∼80% by hepatitis C virus (HCV) infection; the corresponding figures in Korea are ∼70 and ∼20%. Recent clinical data have shown that interferon and lamivudine treatment is effective in preventing the occurrence of HCC attributed to HCV and HBV infection, respectively, and that an aggressive vaccination program against the latter reduces the incidence of HCC. With the enormous efforts of researchers devoted to basic and clinical studies, the incidence of HCC is expected, in the near future, to gradually decline in both countries.

MECHANISM OF SILICA- AND TITANIUM DIOXIDE-INDUCED CYTOTOXICITY IN ALVEOLAR MACROPHAGES

Particles can cause cytotoxicity in pulmonary alveolar macrophages (AM). Several mechanisms to explain this cytotoxicity have been suggested. However, the exact mechanism of particle-induced cytotoxicity in AM remains to be established. Silica and TiO2 produced a concentration-dependent cytotoxicity as evidenced by loss of cell viability and fall in ATP levels. While silica induced a greater cytotoxicity, TiO2 produced a higher reduction in ATP levels. Silica increased the release of LDH, but TiO2 did not affect enzymatic release. TiO2 suppressed succinate-triggered oxygen consumption, whereas silica did not markedly change the effect of succinate on oxygen consumption. Polyinosinic acid (PI), a ligand of the scavenger receptor, inhibited the TiO2-induced fall in ATP content, but could not prevent the effect of silica on cellular ATP content. Data suggest that silica and TiO2 can induce cytotoxicity in AM, probably through different mechanisms.

Expression of Transforming Growth Factor beta - 1 in Chronic Hepatitis and Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection

Background Transforming growth factor beta-1 (TGFβ 1) has been suggested to play a role in the development, growth or progression of hepatocellular carcinoma (HCC). Genotype and serum titer of HCV also affect the occurrence of HCC in chronic hepatitis C. In this study, we were to evaluate the effects of genotype or serum titer of HCV on the expression of TGFβ 1. We also intended to examine the correlation between the up-regulation of TGFβ 1 and the association with HCC in patients with chronic hepatitis C. Methods We studied 19 patients with chronic hepatitis C and 18 with HCC associated with HCV infection. HCV genotype was determined by line probe reverse hybridization assay and the amount of HCV-RNA was quantitated by branched DNA signal amplification assay. Serum TGFβ 1 level was measured by enzyme linked immunosorbent assay. Results HCV genotypes of patients with HCC were similar to those without it. Serum HCV-RNA titer was higher in genotype 1b than in non-1b (p<0.05). Serum TGFβ 1 levels were higher in HCC than in chronic hepatitis (p<0.05). However, there was no significant difference in the serum TGFβ 1 level between genotype 1b and non-1b. Also, it was not correlated with the serum HCV-RNA titer or alanine aminotransferase levels. Conclusion TGFβ 1 seems to be overexpressed in HCC compared to that of chronic hepatitis C; it was not affected by serum ALT levels, genotype or serum HCV titer. It is suggested that TGFβ 1 may be associated with the malignant transformation of hepatocyte or the progression of HCV-associated HCC.

Clevudine therapy for 24 weeks further reduced serum hepatitis B virus DNA levels and increased ALT normalization rates without emergence of viral breakthrough than 12 weeks of clevudine therapy

Objectives: The objectives of the study were to evaluate the safety and antiviral activity of 24-week treatment with clevudine 30 mg in HBeAg(+) chronic hepatitis B patients. Biochemical and serological responses were also assessed. Method: Twenty-one patients received clevudine 30 mg for 24 weeks and were followed up for another 24 weeks off therapy. Results: Median decreases from baseline in HBV DNA were 4.65 and 1.96 log10 copies/ml at week 24 (end of treatment) and week 48 (24 weeks off therapy), respectively. Analysis of individual data showed that HBV DNA levels were below the lower limit of detection (300 copies/ml) by Amplicor PCR assay in 19, 57, 19 and 0% at week 12, 24, 34 and 48, respectively. The proportion of patients with normal ALT were 67, 81 and 75% at week 24 (end of treatment), 34 and 48 (24 weeks off therapy), respectively. The rates of HBeAg loss were 24 and 20% at week 24 and 48, respectively. No viral breakthrough during treatment was observed. Conclusion: Clevudine 30 mg treatment for 24 weeks was well tolerated and exhibited more potent antiviral activity and a higher ALT normalization rate than 12-week treatment with durable efficacy at week 24 off therapy.

Applicability of the BCLC staging system to patients with hepatocellular carcinoma in Korea: analysis at a single center with a liver transplant center

Background/Aims The Barcelona Clinic Liver Cancer (BCLC) staging system is logical for the staging and treatment of hepatocellular carcinoma (HCC) because it was based on survival data. This study evaluated the applicability of the BCLC staging system and reasons for divergence from BCLC-recommended treatments in Korean HCC patients. Methods One hundred and sixty consecutive HCC patients were prospectively enrolled. Treatments were generally recommended according to the guideline of the American Association for the Study of Liver Diseases, but patients were also informed about alternative treatments. The final decision was made with patient agreement, and was based on the doctors preferences when a patient was unable to reach a decision. Results There were 2 (1%), 101 (64%), 20 (12.5%), 34 (21.5%), and 3 (1%) patients with very early-, early-, intermediate-, advanced-, and terminal-stage disease, respectively. Only 64 patients (40%) were treated according to BCLC recommendations. The treatment deviated from BCLC recommendations in 68% (69/101) and 79% (27/34) of patients with early and advanced stage, respectively. The main causes of deviation were refusal to undergo surgery, the presence of an indeterminate malignancy nodule, the absence of a suitable donor, or financial problems. Conclusions Donor shortage, financial problems, the relatively limited efficacy of molecular targeting agents, and the presence of an indeterminate nodule were the main causes of deviation from BCLC recommendations. Even after excluding cases in which decisions were made by patient preference, only 66% of the HCC patients were treated according to BCLC recommendations. Treatment guidelines that reflect the Korean situation are mandatory for HCC patients.

Mucinous ductal ectasia of the pancreas : MRI

Radiologic findings of cystic neoplasms of the pancreas ave been well described (1-4). Itai et al. (5) reported five cases of ductectatic mucinous cystadenoma and cystadenocarcinoma and summarized the radiological features on CT, endoscopic retrograde pancreatography (ERP), and ultrasonography